Isoxazolopyridinones

ABSTRACT

The invention provides compounds of formula I, wherein X, Y, R 1 , R 2 , and R 3  are as defined in the description, and the preparation thereof. The compounds of formula I are useful as pharmaceuticals.

[0001] The present invention relates to novel isoxazolopyridinonederivatives, their preparation, their use as pharmaceuticals andpharmaceutical compositions containing them.

[0002] The invention provides compounds of formula I

[0003] wherein

[0004] either X is O and Y is N

[0005] or X is N and Y is O,

[0006] R₁ is hydrogen, C₁₋₄alkyl, C₃₋₇cycloalkyl,C₃₋₇cycloalkyl-C₁₋₄alkyl or di-C₁₋₄alkylamino-C₁₋₄alkyl,

[0007] R₂ is C₁₋₄alkyl, C₃₋₇cycloalkyl, benzo [1,3]dioxol-5-yl,benzo[1,2,5]oxadiazol-5-yl, benzo[1,2,5]thiadiazol-5-yl or a group offormula (a)

[0008] wherein Z is CH or N, R₄ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxy,halogen, hydroxy, trifluoromethyl, di-C₁₋₄alkylamino, C₁₋₄alkylamino,di-C₁₋₄alkylamino-C₁₋₄alkyl, C₁₋₄alkylamino-C₁₋₄alkyl,di-C₁₋₄alkylamino-C₁₋₄alkoxy, C₁₋₄alkylamino-C₁₋₄alkoxy,di-C₁₋₄alkylamino-C₁₋₄alkoxy-C₁₋₄alkyl,C₁₋₄alkylamino-C₁₋₄alkoxy-C₁₋₄alkyl, di-(C₁₋₄alkoxy-C₁₋₄alkyl)amino,di-(C₁₋₄alkoxy-C₁₋₄alkyl)amino-C₁₋₄alkyl, phenyl, phenoxy, benzyloxyC₁₋₄alkyl, C₁₋₄alkoxy-C₁₋₄alkyl, C₁₋₄-alkoxy-C₁₋₄alkoxy-C₁₋₄alkyl,hydroxy-C₁₋₄alkyl, CHO, carboxy, C₁₋₄alkoxycarbonyl, morpholinomethyl,4-C₁₋₄alkyl-piperazinylmethyl, piperazinylmethyl, tetrazol-1-ylmethyl,1-pyrrolylmethyl, 3-(di-C₁₋₄-alkylamino)-2-hydroxy-propoxy-C₁₋₄alkyl,3-(di-C₁₋₄-alkylamino)-2-hydroxy-propoxy,3-C₁₋₄-alkylamino-2-hydroxy-propoxy-C₁₋₄alkyl,3-C₁₋₄-alkylamino-2-hydroxy-propoxy,2-hydroxy-3-imidazol-1-yl-propoxy-C₁₋₄alkyl,2-hydroxy-3-imidazol-1-yl-propoxy, 2-hydroxy-3-morpholin-4-yl-propoxy,2-hydroxy-3morpholin-4-yl-propoxy-C₁₋₄alkyl, and R₅ and R₆,independently, are hydrogen, halogen, hydroxy, C₁₋₄alkyl or C₁₋₄alkoxy,and

[0009] R₃ is hydrogen, halogen, C₁₋₄alkyl, di-C₁₋₄alkylamino-C₁₋₄alkyl,di-C₁₋₄alkylamino-C₁₋₄alkoxy, C₁₋₄alkylamino-C₁₋₄alkyl,C₁₋₄alkylamino-C₁₋₄alkoxy or C₁₋₄alkoxy,

[0010] in free base or pharmaceutically acceptable acid addition saltform,

[0011] for use in the treatment of Parkinson's disease.

[0012] Any alkyl or alkoxy group as defined above preferably has one ortwo carbon atoms and more preferably is methyl or methoxy.

[0013] Halogen denotes fluorine, chlorine or bromine.

[0014] In a further aspect, the invention provides a process for theproduction of the compounds of formula I and their salts, comprising thestep of reacting a compound of formula II

[0015] wherein R₁ and R₃ are as defined above, with a compound offormula III

R₇-R₂  III

[0016] wherein R₂ is as defined above and R₇ is CHO, CN, CO-Hal, whereinHal is halogen, CON(CH₃)-OCH₃ or morpholinocarbonyl.

[0017] The reaction can be effected according to known methods, forexample as described in Example 1b).

[0018] Compounds of formula I wherein R₂ is a group of formula (a)wherein R₄ is di-C₁₋₄alkylaminomethyl, C₁₋₄alkoxymethyl,di-C₁₋₄alkylamino-C₂₋₄alkoxymethyl, C₁₋₄alkoxy C₂₋₄alkoxymethyl,morpholinomethyl, piperazinylmethyl, 4-C₁₋₄alkylpiperazinylmethyl,tetrazol-1-ylmethyl or 1-pyrrolylmethyl, can also be produced from thecorresponding compounds wherein R₄ is methyl, by bromination followed bynucleophilic substitution, according to conventional procedures, e.g. asdescribed in Example 29.

[0019] Working up the reaction mixtures and purification of thecompounds thus obtained may be carried out in accordance to knownprocedures.

[0020] Acid addition salts may be produced from the free bases in knownmanner, and vice-versa.

[0021] The starting compounds of formula II may be produced fromcarboxylic acids of formula IV

[0022] wherein X, Y and R₃ are as defined above, according to knownprocedures, e.g. as described in Example 1a).

[0023] The starting materials of formulae III and IV are known or may beproduced in analogous manner to known procedures.

[0024] Compounds of formula I and their pharmaceutically acceptable acidaddition salts, hereinafter referred to as agents of the invention,exhibit valuable pharmacological properties where tested in vitro usingNurr1 expressing cell cultures and in vivo, and are therefore useful aspharmaceuticals.

[0025] The nuclear receptor Nurr1 is known to be causally involved inthe functional differentiation of midbrain dopaminergic neurones bothduring development and in adult animals. The defects of dopaminergicneurones observed in the ventral midbrain of Nurr1 knockout animalsresemble the pattern of neuronal degeneration in Parkinson's disease, inwhich the primary motor defects are caused by the degeneration of thesubstantia nigra dopaminergic system (Zetterström et al., 1997; Castilloet al., 1998 and Saucedo-Cardenas et al., 1998). Nurr1 activators aretherefore suggested for preventing or delaying the onset of Parkinsoniansymptoms.

[0026] The affinity of the agents of the invention to the Nurr1 receptorcan be determined in vitro in binding studies:

[0027] Two-dimensional ¹H-¹⁵N correlated spectra (HSQC) are recorded ofuniformly ¹⁵N-labeled ligand binding domain (LBD) of Nurr1 expressed inE. Coli. The spectra provide a fingerprint of the protein structure andchanges in the exact positions of some of the cross peaks in the 2-dspectrum upon titration of a compound indicate ligand binding.

[0028] In this assay, changes in chemical shift are observed in somepeaks at concentrations of 300 μM of the agent of the invention, using50 μM uniformly ¹⁵N-labeled Nurr1 LBD.

[0029] The activity of the agents of the invention at the Nurr1 receptorcan be determined in vitro in cellular assays:

[0030] Induction of the biological activity of the Nurr1 receptor by theagents of the invention can be measured by the transactivation of aNurr1 responsive reporter gene in a midbrain dopaminergic cell line. Theassay is based on the transcription promoting effect of Nurr1. Thereporter gene can be activated both by Nurr1 monomers and Nurr1/RXRheterodimers. RXR is a frequent heterodimerisation partner of nuclearreceptors and it has been shown that Nurr1 can form heterodimers withRXR (Zetterström R H et al. Mol. Endocrinol. 1996; 10:1656-1666).

[0031] In this assay the agents of the invention significantly increasethe reporter gene activity dose dependently at EC₅₀s of about 1 to about1000 nM.

[0032] In vivo, the agents of the invention significantly increasemidbrain dopamine levels at doses of 5 to 30 mg/kg p.o. in the followingassay:

[0033] OF1 mice are treated with the test compound for five days andsacrificed 5 hours after the last compound application. Dopamine levelsare measured in substantia nigra and striatal tissue punches. 10 animalsare treated in each group.

[0034] The agents of the invention are therefore useful in the treatmentof Parkinson's disease.

[0035] For the above-mentioned indication, the appropriate dosage willof course vary depending upon, for example, the compound employed, thehost, the mode of administration and the nature and severity of thecondition being treated. However, in general, satisfactory results inanimals are indicated to be obtained at a daily dosage of from about 0.1to about 500, preferably from about 0.5 to about 100 mg/kg animal bodyweight. In larger mammals, for example humans, an indicated daily dosageis in the range from about 1 to about 500, preferably from about 1 toabout 300 mg of an agent of the invention, conveniently administered,for example, in divided doses up to four times a day or in sustainedrelease form.

[0036] The agents of the invention may be administered in free form orin pharmaceutically acceptable salt form. Such salts may be prepared inconventional manner and exhibit the same order of activity as the freecompounds.

[0037] The agent of the invention may be administered by anyconventional route, in particular enterally, preferably orally, forexample in the form of tablets or capsules, or parenterally, for examplein the form of injectable solutions or suspensions.

[0038] The agents of the invention may alternatively be administerede.g. topically in the form of a cream, gel or the like, or byinhalation, e.g. in dry powder form.

[0039] Examples for compositions comprising an agent of the inventioninclude, e.g. a solid dispersion, an aqueous solution, e.g. containing asolubilising agent, a microemulsion and a suspension of an agent of theinvention. The composition may be buffered to a pH in the range of e.g.from 3.5 to 9.5, by a suitable buffer.

[0040] The agents of the invention can be administered either alone orin combination with other pharmaceutical agents effective in thetreatment of Parkinson's disease.

[0041] Thus, the agents of the invention can be used for the treatmentof Parkinson's disease in combination with, for example, dopamineprecursors (e.g. different levodopa preparations), dopamine agonists(e.g. Bromocriptine, Pramipexole), catechol-O-methyltransferaseinhibitors (e.g. Entacapone, Tolcapone), monoamine oxidase B inhibitors(e.g. Selegiline), NMDA antagonists (e.g. Amantadine) andanticholinergics (e.g. Biperiden, Orphenedrine).

[0042] In accordance with the foregoing, the present invention alsoprovides the use of an agent of the invention, for the manufacture of amedicament for the treatment of Parkinson's disease.

[0043] The preferred agents of the invention include6-(4-dimethylaminomethyl-phenyl)-3-phenyl-5H-isoxazolo[4,5-c]pyridin-4-oneand6-[4-(2-methoxy-ethoxymethyl)-phenyl]-5-methyl-3-phenyl-5H-isoxazolo[4,5-c]pyridin-4-one,in free base or pharmaceutically acceptable acid addition salt form.

[0044] In the above-mentioned in vitro cellular assay, these compoundsincrease the reporter gene activity with EC₅₀s of 70 and 40 nMrespectively. In the above-mentioned in vivo test, they increase thedopamine levels by about 20-30% on administration of 5, 10 and 30 mg/kgp.o.

[0045] In still a further aspect, the invention provides compounds offormula I wherein X, Y, R₁, R₂ and R₃ are as defined above, providedthat

[0046] i) when X is N, Y is O, R₂ is unsubstituted phenyl and R₃ ishydrogen, then R₁ is different from hydrogen, and

[0047] ii) when X is N, Y is O, R₂ is a group of formula (a) whereineither Z is N and R₄ is hydrogen, or Z is CH and R₄ is hydrogen, methyl,methoxy, halogen, trifluoromethyl, p-bromomethyl, p-benzyloxy,dimethylaminomethyl, methylaminomethyl, 4-C₁₋₄alkylpiperazinomethyl,piperidinomethyl or morpholinomethyl and R₃ is hydrogen, chlorine,fluorine, methyl, trifluoromethyl or C₁₋₄alkoxy, then R₁ is differentfrom methyl,

[0048] hereinafter referred to as novel compounds of formula 1.

[0049] The present invention furthermore provides a pharmaceuticalcomposition comprising a novel compound of formula I in free base orpharmaceutically acceptable acid addition salt form, in association withat least one pharmaceutical carrier or diluent. Such compositions may bemanufactured in conventional manner. Unit dosage forms contain, forexample, from about 0.25 to about 150, preferably from 0.25 to about 25mg of the compound.

[0050] The pharmaceutical compositions for separate administration ofthe combination partners and for the administration in a fixedcombination, i.e. a single galenical composition comprising at least twocombination partners according to the invention, can be prepared in amanner known per se and are thus suitable for enteral, such as oral orrectal, and parenteral administration to mammals, including man,comprising a therapeutically effective amount of at least onepharmacologically active combination partner alone or in combinationwith one or more pharmaceutically acceptable carriers, especiallysuitable for enteral or parenteral application.

[0051] In particular, a therapeutically effective amount of each of thecombination partners may be administered simultaneously or sequentiallyand in any order, and the components may be administered separately oras fixed combination.

[0052] Accordingly the invention also provides a combination comprisinga therapeutically effective amount of a novel compound of formula I infree base or pharmaceutically acceptable acid addition salt form and asecond drug substance, said second drug substance being for example foruse in Parkinson's disease.

[0053] Moreover the present invention provides the use of a novelcompound of formula I in free base or pharmaceutically acceptable acidaddition salt form, as pharmaceutical for the treatment of Parkinson'sdisease.

[0054] In still a further aspect the present invention provides a methodfor the treatment of Parkinson's disease in a subject in need of suchtreatment, which comprises administering to such subject atherapeutically effective amount of a novel compound of formula I infree base or pharmaceutically acceptable acid addition salt form.

[0055] The following examples illustrate the invention.

EXAMPLE 1

[0056]5-Methyl-6-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-3-phenyl-5H-isoxazolo[4,5-c]pyridin-4-one:

[0057] a) 5-Methyl-3-phenyl-isoxazole-4-carboxylic acid methylamide:

[0058] To a suspension of 50.0 g (0.25 mol) of5-methyl-3-phenyl-isoxazole-4-carboxylic acid in 1.2 l of1,2-dichloroethane (DCE) is added 1.9 ml dimethyl formamide (DMF) and21.4 ml (0.3 mol, 1.2 eq.) of thionyl chloride. The mixture is stirredfor 2 h at reflux until a clear, yellow solution is formed. The solutionis cooled to room temperature and then slowly added to a 8M solution ofmethylamine in ethanol (146 ml) at 5° C. The suspension is poured ontomethylene chloride, washed with sat. NaHCO₃-solution, dried over Na₂SO₄and concentrated. This yields 52.3 g (99%) of the title compound aslight brown solid, which is used for further reaction withoutpurification. Mass spectrum: m/z (M+H)⁺: 217.1

[0059] b)5-Methyl-6-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-3-phenyl-5H-isoxazolo[4,5-c]pyridin-4-one

[0060] In a 500 ml flask, 10.0 g (46.3 mmol) of5-methyl-3-phenyl-isoxazole-4-carboxylic acid methylamide is suspendedin 150 ml of tetrahydrofuran (THF) under argon. At −70° C. a solution ofbutyl lithium (63 ml, 1.6M in hexane, 101 mmol, 2.2 eq.) is slowlyadded.

[0061] After 1 h at this temperature, the solution is warmed to −10° C.and a solution of 11.9 g (55.5 mmol, 1.2 eq.) of4-(4-methyl-piperazin-1-ylmethyl)-benzonitrile in 80 ml of THF is slowlyadded. Under warming to room temperature, the red solution is stirredfor another hour, then quenched with 2 ml of water and concentrated. Theyellow residue is then taken up in 75 ml of dioxane and kept at 5° C.Then, 230 ml of a 4M solution of HCl in dioxane is carefully added andthe suspension stirred for 20 h at room temperature. Then, the solventis removed and the residue dissolved in ethyl acetate and carefullyneutralised with sat. NaHCO₃-solution. The phases are separated and theorganic phases washed with brine, dried over Na₂SO₄ and concentrated.Chromatographic purification (CH₂Cl₂/MeOH 95:5 to 90:10) yields 7.9 g(41%) of5-methyl-6-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-3-phenyl-5H-isoxazolo[4,5-c]pyridin-4-oneas a white solid. Mass spectrum: m/z (M+H)⁺: 415.0

[0062] According to the procedure described for Example 1, using theappropriate nitrile or Weinreb Amide, the following compounds areprepared:

EXAMPLE 2

[0063]6-Benzo[1,3]dioxol-5-yl-5-methyl-3-phenyl-5H-isoxazolo[4,5-c]pyridin-4-one:This compound is obtained using benzo[1,3]dioxole-5-carbonitrile in 56%as a light yellow solid. Mass spectrum: m/z (M+H)⁺: 347.2

EXAMPLE 3

[0064]6-Biphenyl-4-yl-5-methyl-3-phenyl-5H-isoxazolo[4,5-c]pyridin-4-one: Thiscompound is obtained using biphenyl-4-carbonitrile in 11% as a whitefoam. Mass spectrum: m/z (M+H)⁺: 379.1

EXAMPLE 4

[0065]5-Methyl-3-phenyl-6-pyridin-4-yl-5H-isoxazolo[4,5-c]pyridin-4-one: Thiscompound is obtained using isonicotinonitrile in 59% as a pink solid.Mass spectrum: m/z (M+H)⁺: 304.1

EXAMPLE 5

[0066]6-(4-Diethylamino-phenyl)-5-methyl-3-phenyl-5H-isoxazolo[4,5-c]pyridin-4-one:This compound is obtained using 4-diethylamino-benzonitrile in 11% as abeige solid. Mass spectrum: m/z (M+H)⁺: 374.1

EXAMPLE 6

[0067]5-Methyl-6-(4-phenoxy-phenyl)-3-phenyl-5H-isoxazolo[4,5-c]pyridin-4-one:This compound is obtained using 4-phenoxy-benzonitrile in 44% as a beigesolid. Mass spectrum: m/z (M+H)⁺: 395.0

EXAMPLE 7

[0068]6-[4-2-Methoxy-ethoxymethyl)-phenyl]-5-methyl-3-phenyl-5H-isoxazolo[4,5-c]pyridin-4-one:This compound is obtained usingN-Methoxy-4-(2-methoxy-ethoxymethyl)-N-methyl-benzamide in 58% as awhite solid. Mass spectrum: m/z (M+H)⁺: 391.2

EXAMPLE 8

[0069]5-Methyl-3-phenyl-6-(4-tetrazol-1-ylmethyl-phenyl)-5H-isoxazolo[4,5-c]pyridin-4-one:This compound is obtained using 4-tetrazol-1-ylmethyl-benzonitrile andafter additional RP18-purification in 6% as a white solid. Massspectrum: m/z (M-N₂+H)⁺: 357.1

EXAMPLE 9

[0070] 5-Methyl-3-phenyl-6-p-tolyl-5H-isoxazolo[4,5-c]pyridin-4-one:This compound is obtained using 4-methyl-benzonitrile in 56% as a beigesolid. Mass spectrum: m/z (M+H)⁺: 317.1

EXAMPLE 9a

[0071]6-(3,4-Dimethoxy-phenyl)-5-methyl-3-phenyl-5H-isoxazolo[4,5-c]pyridin-4-one:This compound is obtained using 3,4-dimethoxy-benzonitrile in 11% as abeige solid. Mass spectrum: m/z (M+H)⁺: 363.1

EXAMPLE 9b:

[0072]6-(3,5-Dimethoxy-phenyl)-5-methyl-3-phenyl-5H-isoxazolo[4,5-c]pyridin-4-one:This compound is obtained using 3,5-dimethoxy-benzonitrile in 25% as ayellow resin. Mass spectrum: m/z (M+H)⁺: 363.1

[0073] According to the procedure described for Example 1, usingacetylchloride instead of the nitrile, the following compound isprepared:

EXAMPLE 10

[0074] 5,6-Dimethyl-3-phenyl-5H-isoxazolo[4,5-c]pyridin-4-one: Massspectrum: m/z (M+H)⁺: 241.2

[0075] According to the procedure described for example 1, using theappropriate nitrile or Weinreb Amide,5-methyl-3-phenyl-isoxazole-4-carboxylic acid amide and 3.3 eq. of butyllithium, the following compounds are prepared:

EXAMPLE 11

[0076]6-(4-Dimethylaminomethyl-phenyl)-3-phenyl-5H-isoxazolo[4,5-c]pyridin-4-one:This compound is obtained using 4-dimethylaminomethyl-benzonitrile in25% as a beige solid. Mass spectrum: m/z (M+H)⁺: 346.2

EXAMPLE 12

[0077]6-[4-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-phenyl-5H-isoxazolo[4,5-c]pyridin-4-one:This compound is obtained using4-(4-methyl-piperazin-1-ylmethyl)-benzonitrile in 13% as a solid. Massspectrum: m/z (M+H)⁺: 401.1

EXAMPLE 13

[0078]6-[4-(2-Methoxy-ethoxymethyl)-phenyl]-3-phenyl-5H-isoxazolo[4,5-c]pyridin-4-one:This compound is obtained usingN-Methoxy-4-(2-methoxy-ethoxymethyl)-N-methyl-benzamide in 70% as awhite solid. Mass spectrum: m/z (M+H)⁺: 377.1

[0079] According to the procedure described for example 1, using theappropriate nitrile and 5-methyl-3-phenyl-isoxazole-4-carboxylic acidethylamide, the following compounds are prepared:

EXAMPLE 14

[0080]5-Ethyl-6-(3-methoxy-phenyl)-3-phenyl-5H-isoxazolo[4,5-c]pyridin4-one:This compound is obtained using 3-methoxy-benzonitrile in 28% as asolid. Mass spectrum: m/z (M+H)⁺: 347.2

EXAMPLE 15

[0081]6-Benzo[1,3]dioxol-5-yl-5-ethyl-3-phenyl-5H-isoxazolo[4,5-c]pyridin-4-one:This compound is obtained using benzo[1,3]dioxole-5-carbonitrile in 10%as a solid. Mass spectrum: m/z (M+H)⁺: 361.2

[0082] According to the procedure described for example 1, using theappropriate nitrile and 5-methyl-3-phenyl-isoxazole-4-carboxylic acidpropylamide, the following compound is prepared:

EXAMPLE 16

[0083] 3,6-Diphenyl-5-propyl-5H-isoxazolo[4,5-c]pyridin-4-one: Thiscompound is obtained using benzonitrile in 49% as a solid. Massspectrum: m/z (M+H)⁺: 331.2

[0084] According to the procedure described for example 1, using theappropriate nitrile and 5-methyl-3-phenyl-isoxazole-4-carboxylic acidcyclopropylamide, the following compounds are prepared:

EXAMPLE 17

[0085] 5-Cyclopropyl-3,6-diphenyl-5H-isoxazolo[4,5-c]pyridin-4-one: Thiscompound is obtained using benzonitrile in 17% as a solid. Massspectrum: m/z (M+H)⁺: 329.2

EXAMPLE 18

[0086]6-Benzo[1,3]dioxol-5-yl-5-cyclopropyl-3-phenyl-5H-isoxazolo[4,5-c]pyridin-4-one:This compound is obtained using benzo[1,3]dioxole-5-carbonitrile in 12%as a solid. Mass spectrum: m/z (M+H)⁺: 373.2

EXAMPLE 19

[0087] 5-Methyl-3,6-diphenyl-5H-isoxazolo[4,3-c]pyridin-4-one:

[0088] a) 3-Methyl-5-phenyl-isoxazole-4-carboxylic acid methylamide:

[0089] To a suspension of 6.0 g (29.6 mmol) of3-methyl-5-phenyl-isoxazole-4-carboxylic acid in 150 ml DCE is added 0.3ml of DMF and 2.6 ml (35.5 mmol, 1.2 eq.) of thionyl chloride. Themixture is stirred for 2 h at reflux until a brown solution is formed.The solution is cooled to room temperature and then slowly added to a 8Msolution of methylamine in ethanol (18 ml) at 5° C. The suspension ispoured onto methylene chloride, washed with sat. NaHCO₃-solutlon, driedover Na₂SO₄ and concentrated. This yields 6.7 g (quant.) of the titlecompound as brown solid, which is used for further reactions withoutpurification. Mass spectrum: m/z (M+H)⁺: 217.2

[0090] b) 5-Methyl-3,6-diphenyl-5H-isoxazolo[4,3-c]pyridin-4-one:

[0091] 159 mg (0.73 mmol) of 3-methyl-5-phenyl-isoxazole-4-carboxylicacid methylamide is suspended in 4 ml of THF under argon. At −5° C. asolution of butyl lithium (1.0 ml, 1.6M in hexane, 1.6 mmol, 2.2 eq.) isslowly added. After 1 h at this temperature, the solution is warmed to0° C. and 0.92 ml (0.88 mmol, 1.2 eq.) of benzonitrile is slowly added.Under warming to room temperature, the red solution is stirred foranother 2 h, then quenched with 0.1 ml of water and concentrated. Theresidue is then taken up in 4 ml of a 4M solution of HCl in dioxane andthe suspension stirred for 16 h at room temperature. Then, the solventis removed and the residue dissolved in ethyl acetate and carefullyneutralised with sat. NaHCO₃-solution. The phases are separated and theorganic phases washed with brine, dried over Na₂SO₄ and concentrated.Chromatographic purification (hexane/ethyl acetate 90:10) yields 108 mg(48%) of 5-methyl-3,6-diphenyl-5H-isoxazolo[4,3-c]pyridin-4-one as awhite solid. Mass spectrum: m/z (M+H)⁺: 303.2

[0092] According to the procedure described for example 19, using theappropriate nitrile, the following compounds are prepared:

EXAMPLE 20

[0093]6-(4-Chloro-phenyl)-5-methyl-3-phenyl-5H-isoxazolo[4,3-c]pyridin-4-one:This compound is obtained using 4-chloro-benzonitrile in 54% as a solid.Mass spectrum: m/z (M+H)⁺: 337.2, 339.3

EXAMPLE 21

[0094]5-Methyl-6-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-3-phenyl-5H-isoxazolo[4,3-c]pyridin-4-one:This compound is obtained using4-(4-methyl-piperazin-1-ylmethyl)-benzonitrile in 8% as a solid. Massspectrum: m/z (M+H)⁺: 415.3

[0095] According to the procedure described for example 19, using theappropriate nitrile, 3-methyl-5-phenyl-isoxazole4-carboxylic acid amideand 3.3 eq. of butyl lithium, the following compounds are prepared:

EXAMPLE 22

[0096]6-(4-Dimethylaminomethyl-phenyl)-3-phenyl-5H-isoxazolo[4,3-c]pyridin-4-one:This compound is obtained using 4-dimethylaminomethyl-benzonitrile in 9%as a brown solid. Mass spectrum: m/z (M+H)⁺: 346.2

EXAMPLE 23

[0097]6-[4-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-phenyl-5H-isoxazolo[4,3-c]pyridin-4-one:This compound is obtained using4-(4-Methyl-piperazin-1-ylmethyl)-benzonitrile in 9% as a beige solid.Mass spectrum: m/z (M+H)⁺: 401.2

EXAMPLE 24

[0098]6-(2,4-Dimethoxy-phenyl)-5-methyl-3-phenyl-5H-isoxazolo[4,5-c]pyridin-4-one:To a solution of 216 mg (1.0 mmol) of5-methyl-3-phenyl-isoxazole-4-carboxylic acid methylamide in 5 ml of THFare slowly added 1.4 ml of butyl lithium (1.6M in hexane, 2.2 mmol, 2.2eq.) at −40 ° C. The orange suspension is stirred under warming to roomtemperature for 1 h. Then, at 0° C. 300 mg (1.2 mmol, 1.2 eq.) of2,4-dimethoxy-benzaldehyde is added and the mixture stirred for anotherhour under warming to room temperature. The mixture is quenched with 0.1ml of water and the solvents are removed under reduced pressure. Theresidue is taken up in CH₂Cl₂, washed with sat. NaHCO₃-solution, driedover Na₂SO₄ and concentrated. Purification by flash chromatographyyields 278 mg of a white foam.

[0099] This intermediate is dissolved in 5 ml of acetone, treated with0.55 ml of Jones' reagent (1.1 mmol) and stirred at room temperature for24 h. The mixture is taken up in CH₂Cl₂ and the phases are separated,the aqueous phases is extracted 2 times with CH₂Cl₂, the combinedorganic phases washed with brine and dried over Na₂SO₄ and the solventremoved in vacuo. The residue is then purified over silica gel(hexane/ethyl acetate 8:2 to 1:1) to yield 154 mg (43%) of the titlecompound as white solid. Mass spectrum: m/z (M+H)⁺: 363.1

[0100] According to the procedure described for example 24, using theappropriate isoxazoles and aldehydes, the following compounds areprepared:

EXAMPLE 25

[0101] 6-Cyclohexyl-5-methyl-3-phenyl-5H-isoxazolo[4,5-c]pyridin-4-one:This compound is obtained using 5-methyl-3-phenyl-isoxazole-4-carboxylicacid methylamide and cyclohexanecarbaldehyde in 40% as a beige solid.Mass spectrum: m/z (M+H)⁺: 309.0

EXAMPLE 25a

[0102]6-(2,4-Dimethoxy-phenyl)-5-methyl-3-phenyl-5H-isoxazolo[4,5-c]pyridin-4-one:This compound is obtained using 5-methyl-3-phenyl-isoxazole-4-carboxylicacid methylamide and 2,4-dimethoxy-benzaldehyde in 42% as a white solid.Mass spectrum: m/z (M+H)⁺: 363.1

EXAMPLE 26

[0103]4-(5-Methyl-4-oxo-3-phenyl-4,5-dihydro-isoxazolo[4,3-c]pyridin-6-yl)-benzoicacid methyl ester: This compound is obtained using3-methyl-5-phenyl-isoxazole-4-carboxylic acid methylamide and4-formyl-benzoic acid methyl ester in 15% as a beige solid. Massspectrum: m/z (M+H)⁺: 361.2

EXAMPLE 27

[0104]6-Benzo[1,3]dioxol-5-yl-3-(2-chloro-phenyl)-5-methyl-5H-isoxazolo[4,5-c]pyridin-4-one:This compound is obtained using3-(2-chloro-phenyl)-5-methyl-isoxazole-4-carboxylic acid methylamide andbenzo[1,3]dioxole-5-carbaldehyde in 35% as a beige solid. Mass spectrum:m/z (M+H)⁺: 380.9, 382.9

EXAMPLE 28

[0105] 6-Cyclohexyl-5-ethyl-3-phenyl-5H-isoxazolo[4,5-c]pyridin-4-one:This compound is obtained using 5-methyl-3-phenyl-isoxazole-4-carboxylicacid ethylamide and cyclohexanecarbaldehyde in 20% as a solid. Massspectrum: m/z (M+H)⁺: 323.3

EXAMPLE 29

[0106]5-Methyl-3-phenyl-6-(4-pyrrol-1-ylmethyl-phenyl)-5H-isoxazolo[4,5-c]pyridin-4-one:

[0107] a)6-(4-Bromomethyl-phenyl)-5-methyl-3-phenyl-5H-isoxazolo[4,5-c]pyridin-4-one:At room temperature, 640 mg (2.0 mmol) of5-methyl-3-phenyl-6-p-tolyl-5H-isoxazolo[4,5-c]pyridin-4-one isdissolved in 40 ml of CCl₄. After addition of 34 mg (0.2 mmol, 0.1 eq.)of azoisobutyronitrile, the reaction is heated to reflux and stirred for16 h. After cooling to room temperature, the suspension is taken up inCH₂Cl₂ and washed with 0.1M NaHSO₃-solution and sat. NaHCO₃-solution,dried over Na₂SO₄ and the solvent removed in vacuo to yield 1.1 g(crude, quant.) of a foam, which is used for further reaction withoutpurification. Mass spectrum: m/z (M+H)⁺: 394.9, 396.9

[0108] b)5-Methyl-3-phenyl-6-(4-pyrrol-1-ylmethyl-phenyl)-5H-isoxazolo[4,5-c]pyridin-4-one:

[0109] To a solution of 198 mg (0.5 mmol) of6-(4-bromomethyl-phenyl)-5-methyl-3-phenyl-5H-isoxazolo[4,5-c]pyridin-4-onein 2.5 ml of DMF is added 326 mg (1.0 mmol, 2.0 eq.) of caesiumcarbonate and 0.05 ml (0.6 mmol, 1.2 eq.) of pyrrole. After stirring 16h at room temperature the solvent is removed in vacuo and the residuetaken up in CH₂Cl₂. The organic phase is washed with NaHCO₃-solution,dried over Na₂SO₄ and concentrated. Flash chromatography yields 34 mg(18%) of the desired compound as a white solid. Mass spectrum: m/z(M+H)⁺: 382.1

[0110] According to the procedure described for example 29, replacingpyrrole by the appropriate nucleophile, the following examples areprepared:

EXAMPLE 30

[0111]6-(4-Benzyloxymethyl-phenyl)-5-methyl-3-phenyl-5H-isoxazolo[4,5-c]pyridin-4-one:This compound is obtained using benzyl alcohol in 18% as a white solid.Mass spectrum: m/z (M+H)⁺: 423.0

EXAMPLE 31

[0112]6-(4-Methoxymethyl-phenyl)-5-methyl-3-phenyl-5H-isoxazolo[4,5-c]pyridin-4-one:This compound is obtained using methanol in 27% as a white solid. Massspectrum: m/z (M+H)⁺: 347.3

EXAMPLE 32

[0113]6-[4-(2-Hydroxy-ethoxymethyl)-phenyl]-5-methyl-3-phenyl-5H-isoxazolo[4,5-c]pyrldin-4-one:This compound is obtained using 2-amino-ethanol in 20% as a white solid.Mass spectrum: m/z (M+H)⁺: 404.1

EXAMPLE 33

[0114]6-[4-(2-Hydroxy-ethoxymethyl)-phenyl]-5-methyl-3-phenyl-5H-isoxazolo[4,5-c]pyrdin-4-one:This compound is obtained using ethane-1,2-diol and potassium hydroxideas base in 35% as a clear oil. Mass spectrum: m/z (M+H)⁺: 377.1

1. The use of a compound of formula I

wherein either X is O and Y is N or X is N and Y is O, R₁ is hydrogen,C₁₋₄alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkyl-C₁₋₄alkyl or diC₁₋₄alkylamino-C₁₋₄alkyl, R₂ is C₁₋₄alkyl, C₃₋₇cycloalkyl, benzo[1,3]dioxol-5-yl, benzo[1,2,5]oxadiazol-5-yl,benzo[1,2,5]thiadiazol-5-yl or a group of formula (a)

wherein Z is CH or N, R₄ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxy, halogen,hydroxy, trifluoromethyl, di-C₁₋₄alkylamino, C₁₋₄alkylamino,di-C₁₋₄alkylamino-C₁₋₄alkyl, C₁₋₄alkylamino-C₁₋₄alkyl,di-C₁₋₄alkylamino-C₁₋₄alkoxy, C₁₋₄alkylamino-C₁₋₄alkoxy,di-C₁₋₄alkylamino-C₁₋₄alkoxy-C₁₋₄alkyl,C₁₋₄alkylamino-C₁₋₄alkoxy-C₁₋₄alkyl, di-(C₁₋₄alkoxy-C₁₋₄alkyl)amino,di-(C₁₋₄alkoxy-C₁₋₄alkyl)amino-C_(1,4)alkyl, phenyl, phenoxy, benzyloxyC₁₋₄alkyl, C₁₋₄alkoxy-C₁₋₄alkyl, C₁₋₄alkoxy-C₁₋₄alkoxy-C₁₋₄alkyl,hydroxy-C₁₋₄alkyl, CHO, carboxy, C₁₋₄alkoxycarbonyl, morpholinomethyl,4-C₁₋₄alkyl-piperazinylmethyl, piperazinylmethyl, tetrazol-1-ylmethyl,1-pyrrolylmethyl, 3-(di-C₁₋₄-alkylamino)-2-hydroxy-propoxy-C₁₋₄alkyl,3-(di-C₁₋₄-alkylamino)-2-hydroxy-propoxy,3-C₁₋₄-alkylamino-2-hydroxy-propoy-C₁₋₄alkyl,3-C₁₋₄-alkylamino-2-hydroxy-propoxy,2-hydroxy-3-imidazol-1-yl-propoxy-C₁₋₄alkyl,2-hydroxy-3-imidazol-1-yl-propoxy, 2-hydroxy-3-morpholin-4-yl-propoxy,2-hydroxy-3-morpholin-4-yl-propoxy-C₁₋₄alkyl, and R₅ and R₆,independently, are hydrogen, halogen, hydroxy, C₁₋₄alkyl or C₁₋₄alkoxy,and R₃ is hydrogen, halogen, C₁₋₄alkyl, di-C₁₋₄alkylamino-C₁₋₄alkyl,di-C₁₋₄alkylamino-C₁₋₄alkoxy, C₁₋₄alkylamino-C₁₋₄alkyl,C₁₋₄alkylamino-C₁₋₄alkoxy or C₁₋₄alkoxy, in free base orpharmaceutically acceptable acid addition salt form, for the manufactureof a medicament for the treatment of Parkinson's disease.
 2. A compoundof formula I wherein X, Y, R₁, R₂ and R₃ are as defined in claim 1provided that, i) when X is N, Y is O, R₂ is unsubstituted phenyl and R₃is hydrogen, then R₁ is different from hydrogen, and ii) when X is N, Yis O, R₂ is a group of formula (a) wherein either Z is N and R₄ ishydrogen, or Z is CH and R₄ is hydrogen, methyl, methoxy, halogen,trifluoromethyl, p-bromomethyl, p-benzyloxy, dimethylaminomethyl,methylaminomethyl, 4-C₁₋₄alkylpiperazinomethyl, piperidinomethyl ormorpholinomethyl and R₃ is hydrogen, chlorine, fluorine, methyl,trifluoromethyl or C₁₋₄alkoxy, then R₁ is different from methyl, in freebase or acid addition salt form. 3.6-(4-Dimethylaminomethyl-phenyl)-3-phenyl-5H-isoxazolo[4,5-c]pyridine-4-onein free base or acid addition salt form. 4.6-[4-(2-Methoxy-ethoxymethyl)-phenyl]-5-methyl-3-phenyl-5H-isoxazolo[4,5-c]pyridin-4-onein free base or acid addition salt form.
 5. A process for thepreparation of a compound of formula I as defined in claim 2 or a saltthereof, comprising the step of reacting a compound of formula II

wherein R₁ and R₃ are as defined in claim 2, with a compound of formulaIII R₇-R₂  III wherein R₂ is as defined in claim 2 and R₇ is CHO, CN,CO-Hal, wherein Hal is halogen, CON(CH₃)-OCH₃ or morpholinocarbonyl, andrecovering the resulting compound in free base or acid addition saltform.
 6. A compound of claim 2 in free base or pharmaceuticallyacceptable acid addition salt form, for use as a pharmaceutical.
 7. Apharmaceutical composition comprising a compound of claim 2 in free baseor pharmaceutically acceptable acid addition salt form, in associationwith a pharmaceutical carrier or diluent.
 8. A combination comprising atherapeutically effective amount of a compound of claim 2 in free baseof pharmaceutically acceptable acid addition salt form, and a seconddrug substance, for simultaneous or sequential administration.
 9. Theuse of a compound of claim 2 in free base or pharmaceutically acceptableacid addition salt form, as a pharmaceutical for the treatment ofParkinson's disease.
 10. A method for the treatment of Parkinson'sdisease in a subject in need of such treatment, which comprisesadministering to such subject a therapeutically effective amount of acompound of claim 2 in free base or pharmaceutically acceptable acidaddition salt form.